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Lancet Neurol 2013; 12: 706–15 Vestibular migraine is becoming recognised as a distinct clinical entity that accounts for a high proportion of patients
This online publication has with vestibular symptoms. A temporal overlap between vestibular symptoms, such as vertigo and head-movement
been corrected. intolerance, and migraine symptoms, such as headache, photophobia, and phonophobia, is a requisite diagnostic
The corrected version first
criterion. Physical examination and laboratory testing are usually normal in vestibular migraine but can be used to
appeared at thelancet.com/
neurology on September 15, rule out other vestibular disorders with overlapping symptoms. The pathophysiology of vestibular migraine is
2014 incompletely understood but plausibly could include neuroanatomical pathways to and from central vestibular
Department of Otolaryngology structures and neurochemical modulation via the locus coeruleus and raphe nuclei. In the absence of controlled
(Prof J M Furman MD, trials, treatment options for patients with vestibular migraine largely mirror those for migraine headache.
Prof C D Balaban PhD) and
Department of Anesthesiology
(Prof D A Marcus MD),
Introduction appropriately classified as a type of migraine with aura.4
University of Pittsburgh, Although recurrent vertigo in children was known to be In two groups of patients with basilar-type migraine,
Pittsburgh, PA 15213, USA associated with migraine since Basser’s description in 61–63% reported vertigo as a symptom.5,6 However, few
Correspondence to: 1964,1 in 1984 Kayan and Hood2 alerted the clinical migraine patients with vestibular symptoms meet criteria
Prof Joseph M Furman, community to an important association between for basilar-type migraine.7 Additionally, although some
University of Pittsburgh School
of Medicine, Pittsburgh,
vestibular symptoms and migraine in adults. Since that patients with migraine have vertigo as a premonitory
PA 15213, USA time, appreciation of the role of migraine in the dizzy symptom, the vertigo cannot often be characterised as an
furmanjm@upmc.edu patient has grown. In fact, although a migrainous aura because of its duration or temporal association with
aetiology for vestibular symptoms was previously headache. Thus, with present International Headache
unknown or deemed highly speculative, members of the Society classification criteria, the vestibular symptoms of
International Headache Society in collaboration with many patients with migraine would be deemed unrelated
members of the Barany Society have published diagnostic to migraine. However, most migraine patients with
criteria for a disorder called vestibular migraine.3 As vestibular symptoms do not have a recognised
vestibular migraine is rapidly becoming recognised as a independent vestibular disorder such as Ménière’s
common vestibular disorder, and diagnostic criteria have disease, benign paroxysmal positional vertigo, or
been promulgated, the specialty is poised to make vestibular neuritis. As a result, many patients with both
substantial advances in understanding the patho- migraine and vestibular symptoms do not have a specific
physiology of this disorder and improving its diagnosis to account for their vestibular symptoms. In
management. In this Review, we provide an update response to this deficiency when reaching an accurate
regarding both the clinical aspects of vestibular migraine diagnosis in many migraine patients with vestibular
and the neurobiological basis for the disorder. Our symptoms, Neuhauser and colleagues8 developed
current understanding of vestibular migraine is diagnostic criteria for what is now termed vestibular
rudimentary but continues to evolve. We aim to provide migraine, a disorder in which vestibular symptoms are
both clinicians and clinician-scientists with the latest judged as part of the migrainous disorder itself.
relevant information regarding this frequently en- Nearly 1% of the general population meet these criteria,8
countered disorder and with the latest ideas and basic which is five to ten times higher than the prevalence of
science findings germane to the pathophysiology and Ménière’s disease.9
rational treatment of vestibular migraine. Neuhauser and colleagues’8 criteria for vestibular
migraine have been reassessed favourably in a recent
Diagnostic criteria long-term follow-up paper.10 A structured diagnostic
Patients frequently present with a combination of interview using the criteria11 has been used in studies of
migraine and vestibular symptoms.2 The assessment of the clinical features, epidemiology, genetics, patho-
these patients needs to address the association between physiology, and treatment of vestibular migraine. The
these disorders. That is, are the vestibular symptoms most recent diagnostic criteria for vestibular migraine, a
causally related to a migraine subtype; are the vestibular refinement of the 2001 Neuhauser and colleagues
symptoms and the migrainous symptoms simply a criteria, arose from a working group within the Barany
chance co-occurrence, or is there some more complex Society (panel).3 Recently, Cohen and colleagues12
comorbidity association? Currently, the only Inter- advocated the development of diagnostic criteria by the
national Headache Society migrainous disorder that International Headache Society to account for the
includes vertigo in its classification is basilar-type heterogeneity and natural history of vestibular migraine.
migraine, which is characterised by the occurrence of Internationally proposed diagnostic criteria for vestibular
neurological symptoms originating from the brainstem migraine based on those developed by the Barany Society
or both cerebral hemispheres simultaneously. The and the International Headache Society3 will be included
diagnosis of basilar-type migraine might be more in an appendix of the third edition of the International
migraine might be monogenic and heterogeneous. Von evidence base is available and no randomised controlled
Brevern and colleagues31 found no evidence of an trials for the treatment of vestibular migraine exist, mainly
association between calcium and sodium channel genes because of the hitherto lack of diagnostic criteria. Instead,
linked to familial hemiplegic migraine and episodic treatments are based on those for migraine headache or
ataxia type 2 and vestibular migraine. Lee and colleagues32 are anecdotal. Avoidance of migraine triggers should
found a region on chromosome 11q that is common in always be the first avenue of treatment. Pharmacotherapy
females in a family with vestibular migraine. Bahmad can be abortive, symptomatic for episodes, and
and colleagues33 located a 12·0 MB interval on prophylactic. Although diagnostic criteria for vestibular
chromosome 5q35 that contained a disease gene for migraine are now available, no randomised treatment
familial vestibular migraine. The pathophysiology of this studies have been done, except for a small inconclusive
disease gene remains unknown. study of zolmitriptan as an abortive agent.46 Symptomatic
treatment for acute episodes of vestibular migraine is
Related disorders similar to treatment for acute vertigo with peripheral
Several balance disorders are related to vestibular vestibular causes, including vestibular suppressants such
migraine. Ménière’s disease, benign paroxysmal positional as promethazine, dimenhydrinate, and meclozine.
vertigo, and anxiety are more common in patients with Physical therapy has been reported to improve imbalance
vestibular migraine than would be expected by chance in patients with vestibular migraine in an uncontrolled
alone. The basis for this high comorbidity remains study.47 In general, the scientific literature suggests that
uncertain but might relate to overlaps between the clinical drugs efficacious for prophylaxis of migraine headache
characteristics of these disorders and those of vestibular are also appropriate for prophylaxis of vestibular
migraine, and because vertigo can serve as a migraine migraine.48 On the basis of mainly opinion, and not on
trigger.34 Ménière’s disease and vestibular migraine controlled studies, researchers have advocated β-blockers
overlap extensively in their clinical manifestations, and in such as propranolol or metoprolol; antidepressants such
some patients it might be impossible to establish whether as amitriptyline, nortriptyline, fluoxetine, sertraline, or
they have one or both disorders. Patients with Ménière’s paroxetine; calcium-channel blockers such as verapamil
disease are twice as likely to have migraine as individuals or diltiazem; anticonvulsants such as valproate,
without Ménière’s disease,35 and patients with migraine topiramate, or lamotrigine; and carbonic anhydrase
are more likely to have an earlier onset and bilateral inhibitors such as acetazolamide.49–51
hearing loss with Ménière’s disease.36 Cha and colleagues37
discovered a frequent association among episodic vertigo, Proposed neurobiological bases
migraine, and Ménière’s disease in closely related Present hypotheses of migraine mechanisms are based
individuals. Like patients with Ménière’s disease, patients on results of combined genetic, in-vitro cell biological,
with benign paroxysmal positional vertigo are more likely animal model, and clinical studies in human beings.52–58
to have migraine than patients without benign paroxysmal This well developed published work provides a conceptual
positional vertigo.38 Patients with migraine are also more framework for understanding vestibular migraine as a
likely to have benign paroxysmal positional vertigo than variant produced by the convergence of vestibular
individuals without migraine.39 The highly common information within migraine circuits; therefore, we
finding of persistent rather than paroxysmal positional provide a framework for further development of our
nystagmus in patients with vestibular migraine understanding of vestibular migraine.
complicates this association.22 Psychiatric illness,
especially anxiety and depression, is especially common Vasculature, migraine mechanisms, and the inner ear
in patients with vestibular migraine.40,41 In a prospective The large overlap between migraine pathways and
study of psychiatric illness in vertigo syndromes, only vestibular pathways41,59–61 is consistent with the view that
patients with vestibular migraine had increased rates of vestibular migraine is a migraine variant with vestibular
psychiatric illness 1 year after establishing a vestibular manifestations. Specifically, the vascular, neurogenic
diagnosis.42 Patients with vestibular migraine reported inflammation, and central neural mechanisms that have
more vertigo, more somatic anxiety and autonomic been implicated as peripheral and central triggers of
arousal, and more vertigo-induced handicap than did migraine52–56 are all present in central vestibular pathways
other patients with vertigo.43 Although not strictly a and the inner ear. For example, the trigeminocerebro-
balance disorder, motion sickness susceptibility is more vascular system57 provided a focus to investigate the link
common in patients with migraine in general and patients between vascular responsiveness and pain as a
with vestibular migraine in particular.44,45 physiological consequence of activation of trigeminal
ganglion innervation of cerebral and meningeal
Treatment vasculature. The trigeminovascular system also innervates
Treatment options for patients with vestibular migraine the blood supply of the inner ear.62,63 Iadecola58 provided a
include reduction of triggers, pharmacotherapy, physical more integrative context for migraine mechanisms,
therapy, and mitigation of comorbidities. No dedicated suggesting that a neocortical, extracellular release of
signals (eg, K+, H+, arachidonic acid, and nitric oxide) animals and human beings.83–86 The central constituents
during cortical spreading depression would activate of the migraine circuit include components of central
trigeminal afferents on cranial blood vessels, which would vestibular pathways. For example, the regions affected by
elicit a trigeminovascular reflex-mediated vasodilation in vestibular stimulation in human functional imaging
the meninges via a parasympathetic relay in the studies include those involved in migraine and pain
sphenopalatine ganglion. Simultaneously, as described by perception, such as the posterior insula, anterior insula,
Moskowitz,54 a sterile inflammatory response is elicited orbitofrontal cortex, and the posterior and anterior
from meningeal vessels by peptide secretion from axon cingulate gyri.87–93 Additionally, because the caudal
collaterals of the trigeminal ganglion cells. parabrachial nucleus receives both trigeminal
Parallel events have been observed in the inner ear of nociceptive94–96 and vestibular inputs in rodents and
animals.64,65 The trigeminal innervation of the inner ear primates,97–100 the related pathways might contribute to
seems to be a component of trigeminal innervation of symptoms of vestibular migraine, including motion
other intracerebral blood vessels,62,63,66 and similar effects sensitivity and its interaction with trigeminal pain in
on inner ear blood perfusion have been seen in animal migraine patients.97–104 Furthermore, the high expression
experiments.67–70 Because the trigeminovascular reflex of stress-response receptors in the amygdala and
innervation of the inner ear is one component of the hypothalamus105 suggests a role of stress interactions with
trigeminovascular reflex system, the innervation is a development of migraine signs and symptoms.77
potential site of action for abortive effects of triptans,
ergots, and calcitonin gene-related peptide antagonists on Vestibular processing and migraine circuits
peripheral triggers in patients with vestibular migraine. Vestibular migraine is an example of the integral overlap
Migraine prophylaxis drugs, such as acetazolamide and between vestibular pathways and migraine circuit
topiramate, have the potential to support endolymph triggers and central mechanisms for premonitory
homoeostasis by inhibition of carbonic anhydrase in the symptom generation (figure). Information transmitted
stria vascularis and supporting cells of the sensory by peripheral vestibular sensory organs and the vestibular
epithelia.71,72 The fact that spiral and vestibular ganglion nerve to the medulla and pons is an external trigger
cells in rodents and primates express the main serotonin within the migraine circuit construct proposed by Ho
receptor targets of the triptans and ergots and colleagues.53 Hence, the abortive effects of drugs in
(5-hydroxytryptamine [5-HT]1A, 5-HT1B, 5-HT1D, and 5-HT1F the inner ear (eg, triptans, ergots, calcitonin gene-related
receptors) is interesting because their binding affinities peptide antagonists, non-steroidal anti-inflammatory
are within the clinical dose-related plasma concentrations drugs, lamotrigine, calcium-channel blockers, and
of the drugs.60,73–75 Hence, actions of ganglion cells might topiramate) can attenuate a peripheral trigger specific for
partly explain the efficacy of these agents in vestibular vestibular migraine, and affect a central migraine circuit.
migraine. Finally, the effects of non-steroidal anti- Similarly, the perceptual and sensorimotor consequences
inflammatory drugs might include a blunting of both the of unilateral or bilateral disruptions of peripheral
inflammation and extravasation responses by vestibular function constitute internal triggers of
cyclooxygenase inhibition. vestibular migraine within their framework because the
migraine circuit overlaps extensively with the vestibular-
Integrative migraine mechanisms and vestibular related pathways that have been discussed in the context
pathways: translational rules from basic research of comorbidity of balance disorders, migraine, and
Because vasodilation is neither necessary nor sufficient anxiety disorders.59–61 The central vestibular pathways that
for perception of headache pain,56–58,76 migraine headache overlap with internal trigger mechanisms for the
pain is attributed mainly to central processing of migraine circuit have been parsed conceptually into a
trigeminal afferent activation in ascending thalamocortical cognitive-behavioural component, a neurological
pathways.53,56,58 Specifically, Ho and colleagues53 expanded sensorimotor performance component, and an
the idea of the migraine circuit from strictly trigeminal interoceptive component, which are each modulated by
pathways for vascular regulation and pain perception to a the dorsal raphe nucleus and locus coeruleus (figure).
framework that includes circuits for processing triggers The cognitive-behavioural domain encompasses
and premonitory symptoms. External trigger circuits were vestibulo-thalamo-cortical networks that produce
proposed to include visual, auditory, somatosensory, and perceptual responses to vestibular, visual, proprioceptive,
chemical (olfactory and gustatory) sensory pathways, and and somatosensory afferent inputs. The domain also
contributions from vascular phenomena. Internal triggers includes pathways related to premonitory symptoms
include hormonal fluctuations and stress.77 Both internal associated with balance control, such as circuits involving
and external triggers involve structures such as the the ventral lateral prefrontal cortex, orbitofrontal cortex,
hypothalamus and amygdala, which show altered activity and the ventral aspect of the cingulate cortex that
associated with migraine in functional imaging studies,78–82 communicate with the interoceptive domain for regulation
and contain a dense calcitonin gene-related peptide- of affect. The sensorimotor performance component
positive axon plexus among scattered positive neurons in generates somatic and visceral motor responses to afferent
Amygdala
Vestibular apparatus Vestibular pathways Interoception
Insula Migraine features
Perceptions and sensations
Sensorimotor responses Parabrachial nucleus Premonitory symptoms
• Eye movement
• Head movement
• Postural changes
Autonomic responses Locus coeruleus Dorsal raphe nucleus
Endocrine responses (norepinephrine) (5-hydroxytryptamine)
sensory information. The balance-related sensorimotor intralaminar nuclei including the subparafascicular
component includes brainstem pathways that generate nucleus84,129 and periventricular regions of the
somatic (eg, vestibulo-ocular and vestibulospinal reflexes) hypothalamus. These cells give rise to dense calcitonin
and visceral (vestibulosympathetic and vestibuloparasym- gene-related peptide-immunopositive terminal fields in
pathetic)107,108 motor responses. These vestibular the insular cortex, central amygdaloid nucleus, bed
sensorimotor responses are modulated by the cere- nucleus of the stria terminalis, and the amygdalo-strial
bellum,107,109 which has been activated in human imaging transition region.84 This strong co-localisation of
studies during migraine attacks81,110,111 and shows prominent calcitonin gene-related peptide with central interoceptive
expression of calcitonin gene-related peptide receptors in pathways raises the possibility that central calcitonin
association with Purkinje cells in animals.112 The trigeminal gene-related peptide antagonism is a strategy to both
nociceptive sensorimotor pathways include afferent alter the interpretation of premonitory sensory activity as
sensory thalamocortical pathways, the periaqueductal grey, a symptom and interrupt the progression of external and
and the trigeminovascular reflex circuit. More importantly, internal trigger activity.
neuroanatomical tracing studies have shown extensive The closely connected network between the locus
interconnections among the spinal trigeminal nucleus, coeruleus and dorsal raphe nucleus is a likely target for
vestibular nuclei, and the solitary nucleus100,113–117 and that calcitonin gene-related peptide antagonists and triptans
small cervical dorsal root ganglion cells contribute to in vestibular migraine (figure). This network has the
primary afferent projections to vestibular nuclei.118,119 These potential to modulate vestibular migraine-associated
observations clearly show that the vestibular nuclei premonitory symptoms and triggers of vestibular
contribute to the migraine circuit at the level of the caudal migraine (eg, stress and pain perception) through
brainstem. widespread efferent projections to central migraine and
Interoceptive circuits assess information about present vestibular circuits. The locus coeruleus and the dorsal
sensory and motor processes relative to the physiological raphe nucleus have long been included as modulators of
status of the individual,120 and translate this information both central migraine circuits52,56 and vestibular
into subjective awareness and feelings (often termed the sensorimotor130–134 and interoceptive circuits.59–61 Locus
sentient self).121 Interoceptive circuits for vestibular, coeruleus unit activity in rats and monkeys increases with
visceral sensory, and nociceptive information include a exposure to novel or imperative sensory stimuli,
network that contains the parabrachial nucleus, central particularly during reorientation of attention in contexts
amygdaloid nucleus, and bed nucleus of the stria associated with stress or anxiety.135–137 A large proportion of
terminalis, several posterior thalamic intralaminar nuclei, locus coeruleus neurons are immunoreactive for
the hypothalamus, and the insular cortex. Neuroanatomical calcitonin gene-related peptide in mammals (including
studies have shown that this network is notable for its human beings)84,125,138 and express the stress response-
large concentration of calcitonin gene-related peptide related corticotropin-releasing hormone, glucocorticoid,
immunoreactive neurons,84,122–125 which include regions and mineralocorticoid receptors.105 The dorsal raphe
related to visceral, vestibular, and nociceptive pathways nucleus neurons do not show appreciable calcitonin
in the rostrodorsal and caudoventral parabrachial gene-related peptide expression but do express
nucleus,94,95,97,98,100,126–128 several posterior thalamic corticotrophin-releasing hormone and mineralocorticoid
receptors highly.105 Raphe neurons and their targets also is plausible for lamotrigine, calcium-channel blockers,
express 5-HT1B and 5-HT1D receptors,139,140 which provide and topiramate153 in the attenuation of peripheral trigger
both presynaptic and postsynaptic targets for triptans. susceptibility in vestibular migraine.
Activity of the dorsal raphe nucleus seems to be associated
with the selection of a behavioural strategy to either act or Conclusions and future directions
orient and gather more information. Activation of the Vestibular migraine is becoming recognised as a highly
dorsal raphe nucleus in rats and monkeys accompanies prevalent vestibular disorder that is a subtype of migraine.
facilitated motor activity, inhibited sensory information Recently developed diagnostic criteria have helped clinical
processing, and concomitant expression of hormonal and research, allowing a more complete understanding of the
neuroendocrine activity.141 During orienting responses, clinical aspects of vestibular migraine. The challenge now
reduced activity of these neurons occurs in conjunction is to better understand the pathophysiology of vestibular
with motor activity disfacilitation and sensory processing migraine from both a clinical and basic science
disinhibition. Hence, the interplay between the locus perspective to enable improved rational management of
coeruleus and dorsal raphe nucleus might modulate this disorder. Recent studies of vestibular psychophysics154
perceptual and trigger-related activity in migraine circuits. and motion sickness susceptibility155–157 in vestibular
migraine are yielding exciting new insights. An expanded
Cav2.1 channels and the sodium–potassium ATPase α2 view of the migraine circuit motivates basic science
subunit studies of the individual and interactive roles of vestibular
In view of the many components of the migraine and and nociceptive mechanisms in vestibular migraine. For
vestibular migraine circuits, it is not surprising that example, studies of the role of inner ear trigeminovascular
identification of one major susceptibility locus has been reflexes in blood flow regulation, endolymph-perilymph
elusive in genetic linkage studies.30,31 However, some homoeostasis, vestibular transduction, and vestibular
candidate mutations from family association studies affect nerve function are needed to develop rules for
molecules in the inner ear (peripheral trigger mechanisms) understanding the different effects of drugs on the
and the brain. For example, functional mutations of a vestibular symptoms and headache. Additionally, basic
neuronal voltage-gated calcium channel (Cav2.1) in studies are needed to elucidate neuronal processing
familial hemiplegic migraine type 1 and the glial catalytic interactions between nociceptive and vestibular
α2 subunit of sodium–potassium ATPase (NaKA α2) in information processing, interactions of nociceptive and
familial hemiplegic migraine type 2 have been discussed vestibular processing with stress-related receptor
in the framework of neuron-glial-vascular contributions mechanisms—eg, arginine vasopressin, corticotrophin-
(neurovascular unit142,143) to cortical spreading depression.144 releasing hormone, glucocorticoid and mineralocorticoid
However, the Cav2.1 (P/Q type) channels have many receptors105 in migraine circuits—and the effects of
potential roles in vestibular migraine. Experiments in antimigraine medications on vestibular nerve and
animals show that these channels are mediators of the vestibular nucleus activity. Finally, in view of the parallel
trigeminovascular reflex145 and they can modulate neurochemical organisation of pain and vestibular
transmission at dural trigeminocervical afferent relays in pathways, it will be fruitful to investigate the common
the spinal cord.146 Additionally, Cav2.1 channels help genetic bases for vestibular migraine, craniofacial pain158
regulate calcitonin gene-related peptide release from and interactions between stress and pain,159 including
neuronal processes in the dura, trigeminal ganglion, and pharmacogenetic features that might affect drug
the spinal trigeminal nucleus.147 The same effect is likely efficacy.160 These studies will provide essential new
in the inner ear trigeminovascular terminals. Other knowledge to guide controlled treatment trials for
mutations of Cav2.1 are associated with vertigo in episodic vestibular migraine.
ataxia type 5 (CACNB4 mutation) or vertigo plus migraine
in episodic ataxia type 2 (CACNA1A mutation).30 Reduced
otolithocular function is also associated with CACNA1A Search strategy and selection criteria
mutations in patients with episodic ataxia type 2 and We searched Medline for articles in English published
spinocerebellar ataxia type 6.30 The trigeminal ganglion,148 between Jan 1, 1980, and Dec 31, 2012, with the search
vestibular ganglion,149 and spiral ganglion150 express Cav2.1 words: “migraine”, “dizziness”, “vertigo”, “vestibular”,
mRNA in rodents, suggesting that mutations can “balance”, and “headache”. Terms were expanded using the
potentially affect both the fifth and eighth cranial nerves. ‘exp’ (explode) function and the Boolean ‘AND’ function was
Immunoreactivity for NaKA α2, on the other hand, is used to select subsets. Studies of human beings and animals
associated with fibrocytes below vestibular sensory were included. Both original research and review articles were
epithelia and in the cochlea.72,151 Hence, the antimigraine included. Additional citations were obtained by searching for
actions of the butterbur root sesquiterpenes S-petasin, iso- additional articles by first authors of articles identified
S-petasin, and eudesmol might show preferential actions through the primary search and by reviewing citation lists
as use-dependent antagonists of the Cav2.1 channel152 in within retrieved papers.
vestibular ganglion cells. A similar mechanism of action
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